Understanding the anti-inflammatory and pro-resolving functions of micronutrient selenium (Se) incorporated as the 21st amino acid, selenocysteine (Sec), into selenoproteins may hold the key to controlling gastrointestinal (GI) homeostasis in patients with inflammatory bowel disease (IBD). Despite advances, complete mucosal healing remains a difficult treatment target for many patients with IBD. Localized response to injury involves first responders, polymorphonuclear cells (neutrophils; PMNs), and macrophages that not only display an inflammatory phenotype, but also aid in resolving inflammation via efferocytosis of apoptotic PMNs, to initiate a cascade of pro-resolution events involving metabolic reprogramming. We have demonstrated an essential role for selenoproteins in effectively shunting pathways of arachidonic acid (ARA) metabolism in macrophages to effect resolution by skewing macrophage polarization towards an anti-inflammatory/pro-resolutory (M2) phenotype. Selenoprotein-dependent differential modulation of transcription factors, nuclear factor (NF)-¿B and peroxisome proliferator activated receptor (PPAR)-¿, led to eicosanoid class switching resulting in decreased cyclooxygenase (COX)-derived pro-inflammatory prostaglandin E2 (PGE2) and high PGD2 and its anti-inflammatory and pro-resolutory cyclopentenone prostaglandins (CyPGs) metabolites, ¿12-prostaglandin J2 and 15-deoxy-¿12,14-PGJ2, in three models of GI injury involving chemical injury with dextran sodium sulfate, enteric infection with bacterium Citrobacter rodentium and helminthic parasite, Nippostrongylus brasiliensis. In these models, macrophage selenoprotein expression was key to mitigating inflammation and increasing the polarization of classically activated (M1) to pro-resolving alternatively activated (M2)-like cells that was dependent on CyPG production suggesting resolution. Our studies led us to a selenoprotein, SelenoW, a highly expressed selenoprotein in macrophages in response to dietary Se supply. Apart from its function in cell cycle regulation, the role of SelenoW in GI inflammation and resolution is not well understood. Clinical data indicated that SelenoW levels in inflamed colonic tissue of ulcerative colitis patients were decreased along with PGD2 levels compared to healthy controls and those in active remission, respectively. Guided by exciting feasibility data, we hypothesize that regulation of SelenoW expression by dietary Se and/or other transcriptional mechanisms, mediated by CyPGs, may hold a key to increasing pro-resolution mechanisms to ultimately effect mucosal healing from GI injury. We will test the hypothesis in murine models lacking SelenoW to: 1) Examine the role of SelenoW in resolution of GI inflammation; 2) Examine the role of SelenoW in the interaction of macrophages and PMNs during resolution of inflammation; and 3) Examine the role of SelenoW in metabolic adaptation during resolution of inflammation. Successful completion of these studies will provide new information highlighting the interplay between specific selenoproteins and pathways of resolution of inflammation, essential to increase our understanding of the role of dietary Se in optimal gut health.